TOFA analogs useful in treating dermatological disorders or conditions

Abstract

This invention is directed to analogs of 5-(tetradecyloxy)-2-furancarboxylic acid (TOFA) and their use in the treatment of dermatological disorders or conditions characterized by sebaceous gland hyperactivity, such as acne and oily skin, and other dermatological disorders and conditions. This invention is also directed to pharmaceutical compositions comprising analogs of TOFA and a pharmaceutically acceptable excipient for dermatological or oral administration.

The invention claimed is: 
     
       1. A method for treating a dermatological disorder or condition in a human in need thereof comprising: administering to the human a therapeutically effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is —O—R 2 , or —O—R 3 —C(O)N(R 5 )R 6 ; 
 R 2  is haloalkyl or aryl optionally substituted with —COOH; 
 R 3  is independently an optionally substituted alkylene chain; and 
 R 4  is optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl; 
 R 5  is independently hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted aralkyl; and 
 R 6  is alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl or —R 3 —C(O)OR 4 ; 
 or any R 5  and R 6 , together with the nitrogen to which they are both attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; as a single stereoisomer or as a mixture thereof; or as a pharmaceutically acceptable salt, or as a part of a pharmaceutical composition. 
 
       
     
     
       2. The method of  claim 1  wherein treating dermatological disorder or condition comprising inhibiting sebaceous gland activity. 
     
     
       3. The method of  claim 1  wherein the dermatological disorder or condition is acne vulgaris, acne conglobata, choracne, rosacea, Rhinophyma-type rosacea, seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, or oily skin. 
     
     
       4. The method of  claim 1  wherein the administering to the human comprises topically applying the compound of Formula (I) to the human. 
     
     
       5. The method of  claim 1  wherein
 R 1  is —O—R 2 ; and 
 R 2  is haloalkyl or aryl optionally substituted with —COOH, 
 as a single stereoisomer or as a mixture thereof; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
       6. The method of  claim 5  wherein the compound of Formula (I) is selected from:
 2,2,2-trifluoroethyl 5-(tetradecyloxy)furan-2-carboxylate; 
 2,2,2-trichloroethyl 5-(tetradecyloxy)furan-2-carboxylate; 
 2-bromoethyl 5-(tetradecyloxy)furan-2-carboxylate; and 
 2-(5-(tetradecyloxy)furan-2-carbonyloxy)benzoic acid. 
 
     
     
       7. The method of  claim 1  wherein
 R 1  is —O—R 3 —C(O)N(R 5 )R 6 ; 
 R 3  is an alkylene chain; and 
 R 4  is alkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl; 
 R 5  is hydrogen, alkyl, cycloalkyl, aryl or aralkyl; and 
 R 6  is alkyl, cycloalkyl, aralkyl or —R 3 —C(O)OR 4 ; 
 or R 5  and R 6 , together with the nitrogen to which they are both attached, form an N-heterocyclyl or N-heteroaryl, each of which being optionally substituted with cycloalkyl, aryl or —C(O)OR 4 . 
 
     
     
       8. The method of  claim 7  wherein the compound of Formula (I) is selected from:
 2-(benzyl(methyl)amino)-2-oxoethyl 5-(tetradecyloxy)furan-2-carboxylate; 
 tert-butyl 4-(2-(5-tetradecyloxy)furan-2-carbonyloxy)acetyl)piperazine-1-carboxylate; 
 2-(dicyclohexylamino)-2-oxoethyl 5-(tetradecyloxy)furan-2-carboxylate; 
 2-(4-cyclohexylpiperazin-1-yl)-2-oxoethyl 5-(tetradecyloxy)furan-2-carboxylate; 
 2-oxo-2-(4-phenylpiperzin-1-yl)ethyl-5-(tetradecyloxy)furan-2-carboxylate; 
 2-((2-ethoxy-2-oxoethyl)(methyl)amino)-2-oxoethyl 5-tetradecyloxy)furan-2-carboxylate; 
 2-oxo-2-(piperidin-1-yl)ethyl-5-(tetradecyloxy)furan-2-carboxylate; 
 2-morpholino-2-oxoethyl 5-(tetradecyloxy)furan-2-carboxylate; 
 2-(3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl 5-(tetradecyloxy)furan-2-carboxylate; and 
 (S)-benzyl 1-(2-(5-(tetradecyloxy)furan-2-carbonyloxy)acetyl)pyrrolidine-2-carboxylate. 
 
     
     
       9. A method for treating acne vulgaris in a human in need thereof comprising: applying to the human a topical formulation comprising 2-((2-ethoxy-2-oxoethyl)(methyl)amino)-2-oxoethyl 5-tetradecyloxy)furan-2-carboxylate. 
     
     
       10. The method of  claim 8  comprising applying the topical formulation on acne vulgaris on the human's face. 
     
     
       11. A method for treating a human having a disorder or condition characterized by inflammation comprising: administering to the human a therapeutically effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is —O—R 2 , or —O—R 3 —C(O)N(R 5 )R 6 ; 
 R 2  is haloalkyl or aryl optionally substituted with —COOH; 
 R 3  is independently an optionally substituted alkylene chain; and 
 R 4  is optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl; 
 R 5  is independently hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted aralkyl; and 
 R 6  is alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl or —R 3 —C(O)OR 4 ; 
 or any R 5  and R 6 , together with the nitrogen to which they are both attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; as a single stereoisomer or as a mixture thereof; or as a pharmaceutically acceptable salt, or as a part of a pharmaceutical composition. 
 
       
     
     
       12. The method of  claim 11  wherein the disorder or condition is inflammatory acne. 
     
     
       13. The method of  claim 11  wherein treating the human having a disorder or condition characterized by inflammation comprises reducing T cell proliferation and cytokine secretion in the human. 
     
     
       14. The method of  claim 11  wherein
 R 1  is —O—R 2 ; and 
 R 2  is haloalkyl or aryl optionally substituted with —COOH, 
 as a single stereoisomer or as a mixture thereof; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
       15. The method of  claim 14  wherein the compound of Formula (I) is selected from:
 2,2,2-trifluoroethyl 5-(tetradecyloxy)furan-2-carboxylate; 
 2,2,2-trichloroethyl 5-(tetradecyloxy)furan-2-carboxylate; 
 2-bromoethyl 5-(tetradecyloxy)furan-2-carboxylate; and 
 2-(5-(tetradecyloxy)furan-2-carbonyloxy)benzoic acid. 
 
     
     
       16. The method of  claim 11  wherein
 R 1  is —O—R 3 —C(O)N(R 5 )R 6 ; 
 R 3  is an alkylene chain; and 
 R 4  is alkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl; 
 R 5  is hydrogen, alkyl, cycloalkyl, aryl or aralkyl; and 
 R 6  is alkyl, cycloalkyl, aralkyl or —R 3 —C(O)OR 4 ; 
 or R 5  and R 6 , together with the nitrogen to which they are both attached, form an N-heterocyclyl or N-heteroaryl, each of which being optionally substituted with cycloalkyl, aryl or —C(O)OR 4 . 
 
     
     
       17. The method of  claim 16  wherein the compound of Formula (I) is selected from:
 2-(benzyl(methyl)amino)-2-oxoethyl 5-(tetradecyloxy)furan-2-carboxylate; 
 tert-butyl 4-(2-(5-tetradecyloxy)furan-2-carbonyloxy)acetyl)piperazine-1-carboxylate; 
 2-(dicyclohexylamino)-2-oxoethyl 5-(tetradecyloxy)furan-2-carboxylate; 
 2-(4-cyclohexylpiperazin-1-yl)-2-oxoethyl 5-(tetradecyloxy)furan-2-carboxylate; 
 2-oxo-2-(4-phenylpiperzin-1-yl)ethyl-5-(tetradecyloxy)furan-2-carboxylate; 
 2-((2-ethoxy-2-oxoethyl)(methyl)amino)-2-oxoethyl 5-tetradecyloxy)furan-2-carboxylate; 
 2-oxo-2-(piperidin-1-yl)ethyl-5-(tetradecyloxy)furan-2-carboxylate; 
 2-morpholino-2-oxoethyl 5-(tetradecyloxy)furan-2-carboxylate; 
 2-(3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl 5-(tetradecyloxy)furan-2-carboxylate; and 
 (S)-benzyl 1-(2-(5-(tetradecyloxy)furan-2-carbonyloxy)acetyl)pyrrolidine-2-carboxylate.